Next generation sequencing to identify novel colorectal cancer genes

下一代测序鉴定新的结直肠癌基因

基本信息

批准号：
8862434
负责人：
Chad Daniel Huff
金额：
$ 66.98万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-05 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8862434
关键词：
APC gene Accounting Adenomatous Polyposis Coli African American Age Age of Onset Area Under Curve Cancer Center Cancer Etiology Candidate Disease Gene Caucasians Cessation of life Chemopreventive Agent Clinical Collaborations Colorectal Cancer Complex DNA Development Disease Epidemiologic Factors Ethnic Origin Etiology Family Family history of Frequencies Gender Gene Frequency Gene Targeting Genes Genetic Genetic Predisposition to Disease Genome Goals Health Health Benefit Hereditary Nonpolyposis Colorectal Neoplasms Heritability Hispanic Americans Individual Intervention MLH1 gene MSH2 gene MSH6 gene Malignant Neoplasms Measures Mendelian disorder Minor Mismatch Repair Modeling Mutation Not Hispanic or Latino Nucleotides Oncogenes Open Reading Frames PMS2 gene Penetrance Performance Phenotype Physicians Play Population Predisposition Prevention strategy Public Health Recording of previous events Research Design Resources Risk Sample Size Sampling Signal Transduction Staging Susceptibility Gene Syndrome Targeted Resequencing Testing United States Universities Utah Validation Variant Woman base cancer risk cancer type colon cancer patients design exome exome sequencing genetic risk factor genetic variant genome wide association study genotyping technology high risk improved insight lifetime risk men next generation sequencing novel novel diagnostics patient population population based predictive modeling prognostic rare variant risk variant screening targeted sequencing tool

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. Driven by common disease common variants hypothesis, genome-wide association studies only identified a number of common susceptibility loci that explained a small portion of CRC heritability. The goal of this project is to identify rare genetic variants with intermediate effect size that predispose individuals to colorectal cancer through a next generation sequencing approach. This proposal builds upon a rich resource of the large CRC patient population at MD Anderson Cancer Center and a population-based resource at University of Utah. There are four specific aims. The first aim is to identify novel susceptibility genes for CRC by conducting whole exome sequencing in 500 cases and 500 controls from MD Anderson. The extreme phenotype study design will be used to enrich the cases by family history of CRC and/or early age of onset. This enrichment of genetic component in the cases will enable us to have sufficient power to identify potential disease causing rare variants with th current sample size. For rare variants (MAF < 5%), we will employ the gene-based approach to facilitate identification of rare variants associated with the risk of CRC. The second aim is to internally validate the top 1,000 genes by targeted sequencing in an additional 4,400 samples from MD Anderson. The third aim is to externally validate the top 100 genes in an additional 1,500 samples from University of Utah and further examine these 100 genes in 400 African American (AA) CRC cases and 400 AA Controls and 400 Hispanic American (HA) cases and 400 HA controls from MD Anderson by targeted sequencing. The fourth aim is to build quantitative risk prediction model by incorporating epidemiologic factors, exposure factors, and genetic factors for the risk of CRC. This study will provide significant insight in the etiology of CRC and improve our understandings of the genetic basis of CRC. The prediction model will enable us to identify genetically susceptible individuals at high-risk of developing CRC who would benefit from intensive screening and/or chemopreventive interventions. It is of immense clinical and public health benefit.

描述（由申请人提供）：结直肠癌（CRC）是美国与癌症相关死亡的第二大原因。在普通疾病的普通变异假设的驱动下，全基因组关联研究仅确定了许多共同的易感基因座，这些基因座解释了一小部分CRC遗传力。该项目的目的是确定稀有遗传具有中间作用大小的变体通过下一代测序方法使个体易于结直肠癌。该提案基于MD安德森癌症中心大量CRC患者人群的丰富资源以及犹他大学的基于人群的资源。有四个具体目标。第一个目的是确定新颖的敏感性通过在500例病例中进行整个外显子组测序和MD Anderson的500个对照，用于CRC的基因。极端的表型研究设计将通过CRC的家族史和/或发病时代的家族病史来丰富病例。在此情况下，这种遗传成分的富集将使我们拥有足够的能力来鉴定潜在的疾病，从而导致稀有的变体具有当前样本量的稀有变体。对于稀有变体（MAF <5％），我们将采用基于基因的方法来促进与CRC风险相关的稀有变体。第二个目的是通过在MD Anderson的另外4,400个样本中进行靶向测序来内部验证前1000个基因。第三个目的是在犹他大学的另外1,500个样品中验证前100个基因，并进一步检查400名非裔美国人（AA）CRC病例和400个AA对照组和400个西班牙裔美国人（HA）病例（HA）病例和400例HA对照组中的这100个基因，并通过靶向测序从MD和MD和MD和MD和SERSORS进行了400个HA对照。第四个目的是通过纳入CRC风险的流行病学因素，暴露因素和遗传因素来建立定量风险预测模型。这项研究将为病因提供重大见解 CRC并提高我们对CRC遗传基础的理解。预测模型将使我们能够在高风险的CRC中确定遗传易感人群，这些人将受益于密集筛查和/或化学预防干预措施。它具有巨大的临床和公共卫生益处。